Species-Specific Paternal Age Effects and Sperm Methylation Levels of Developmentally Important Genes

Abstract

A growing number of sperm methylome analyses have identified genomic loci that are susceptible to paternal age effects in a variety of mammalian species, including human, bovine, and mouse. However, there is little overlap between different data sets. Here, we studied whether or not paternal age effects on the sperm epigenome have been conserved in mammalian evolution and compared methylation patterns of orthologous regulatory regions (mainly gene promoters) containing both conserved and non-conserved CpG sites in 94 human, 36 bovine, and 94 mouse sperm samples, using bisulfite pyrosequencing. We discovered three (NFKB2, RASGEF1C, and RPL6) age-related differentially methylated regions (ageDMRs) in humans, four (CHD7, HDAC11, PAK1, and PTK2B) in bovines, and three (Def6, Nrxn2, and Tbx19) in mice. Remarkably, the identified sperm ageDMRs were all species-specific. Most ageDMRs were in genomic regions with medium methylation levels and large methylation variation. Orthologous regions in species not showing this age effect were either hypermethylated (>80%) or hypomethylated (<20%). In humans and mice, ageDMRs lost methylation, whereas bovine ageDMRs gained methylation with age. Our results are in line with the hypothesis that sperm ageDMRs are in regions under epigenomic evolution and may be part of an epigenetic mechanism(s) for lineage-specific environmental adaptations and provide a solid basis for studies on downstream effects in the genes analyzed here.

DNA Demethylation of Myogenic Genes May Contribute to Embryonic Leg Muscle Development Differences between Wuzong and Shitou Geese

“…A similar correlation was found in the pig longissimus dorsi muscle, where a global loss of DNA methylation in the gene body region in skeletal muscle of middle-aged pigs was found compared with the young group [ 22 ]. Similar to this study, species-specific or breed-specific DNA methylation patterns were also observed when comparing human, bovine, and mouse DNA methylation patterns [ 23 ]. In this study, we found that gene expression and DNA methylation were negatively correlated only in regulatory regions around TSSs.…”

Age-related methylation changes in the human sperm epigenome

“…In a candidate gene study [ 39 ], we identified three sperm ageDMRs in humans, four in bovine, and three in mice, which were all species-specific. Here, we show a species-specific effect of paternal age on HSA19, which has not been conserved in the marmoset.…”

Harnessing male germline epigenomics for the genetic improvement in cattle

“…Breed-specific HMRs of three commercial pig breeds are also reported to be related to phenotypic changes [ 49 ]. Interestingly, age-related differentially methylated regions (ageDMRs) were reported to be largely species-specific based on bisulfite pyrosequencing data from 10 regions [ 50 ]. The authors stipulated that ageDMRs in the epigenomic evolution regions may explain the lineage-specific environmental adaptations and predict the age-dependent sperm-related traits.…”